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Genes Cells. 2006 Jun;11(6):685-700.

Transgenic rescue of erythroid 5-aminolevulinate synthase-deficient mice results in the formation of ring sideroblasts and siderocytes.

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Research Laboratory for Molecular Genetics, Yamagata University, Yamagata 990-9585, Japan.


Molecular defects in erythroid 5-aminolevulinate synthase (ALAS-E), the first enzyme in the heme biosynthetic pathway, cause X-linked sideroblastic anemia (XLSA). However, ring sideroblasts, the hallmark of XLSA, were not found in ALAS-E-deficient mouse embryos, indicating that simple ALAS-E-deficiency is not sufficient for ring sideroblast formation. To investigate the developmental stage-specific pathogenesis caused by heme-depletion, we attempted a complementation rescue of ALAS-E-deficiency. We exploited transgenic mouse lines expressing human ALAS-E at approximately half that of wild-type levels. In these hypomorphic embryos, most of the primitive erythroid cells were transformed into ring sideroblasts. The majority of the circulating definitive erythroid cells became siderocytes, enucleated erythrocytes containing iron deposits, and definitive ring sideroblasts were also observed. These iron-overloaded cells suffered from an alpha/beta globin chain imbalance. Despite the iron overload, transferrin receptors were highly expressed in the erythroid cells, suggesting they contribute to the formation of ring sideroblasts and siderocytes. These results indicate that a partially depleted heme supply provokes ring sideroblast formation. The experimental generation of ring sideroblasts in animals would contribute to our understanding of the iron metabolism and its disorder in erythroid cells.

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